The present invention relates to derivatives of piperazine having the general formula (I): ##STR3## wherein R.sub.1 is benzhydryl or cinnamyl, and R.sub.2 is selected from the group consisting of --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4, ##STR4## --(CH.sub.2).sub.3 --R.sub.8, --CH.sub.2 NHR.sub.9, --CH.sub.2 NH.sub.2 and --COR.sub.10, wherein R.sub.3 is hydrogen, chloromethyl, (4-benzhydryl-1-piperazinyl) methyl, 4-morpholinylmethyl or 1-piperidinylmethyl,
R.sub.4 is a hydrogen, chloromethyl or carbethoxy, PA1 R.sub.5 and R.sub.6 together can be an oxygen atom or the sequence --O--(CH.sub.2).sub.2 --O--, PA1 R.sub.7 is methyl, phenyl or 2-thienyl, PA1 R.sub.8 is 4-morpholinyl, 1-piperidinyl or 4-benzhydryl-1-piperazinyl, PA1 R.sub.9 is 2-oxo-1-(pyrrolidinyl) acetyl, 2-hydroxybenzoyl or 4-sulfamoylbenzoyl, PA1 R.sub.10 is 2-oxo-1-(pyrrolidinyl) methyl or 4-sulfamoylphenyl and X is oxygen or NH,
The invention further relates to the non-toxic addition salts of compound I as well as to a method for making the same and to their use in a pharmaceutical composition.
The compounds of the present invention are obtained in accordance with the following methods:
(A) Reacting a monalkyl piperazine of general formula (II): ##STR5## wherein R.sub.1 is as defined for (I), with a reactant selected from an alkyl halide of general formula Y-R.sub.11 (III) wherein Y is chlorine or bromine and R.sub.11 is --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4, ##STR6## or --(CH(.sub.2).sub.3 --R.sub.8, X is oxygen or NH, thus obtaining the compounds of general formula (I) wherein R.sub.1 is defined above and R.sub.2 is selected from --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4, ##STR7## or --(CH.sub.2).sub.3 --R.sub.8, X is Oxygen or NH.
Likewise, the reaction of compounds of general formula (I) wherein R.sub.1 is as defined and R.sub.2 is --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4 (R.sub.3 =chloromethyl, R.sub.4 =hydrogen) with N-monobenzhydrylpiperazine, morpholine or piperidine yields the compounds of general formula (I) wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4 (R.sub.3 =(4-benzhydryl-1-peperazinyl)methyl, 4-morpholinylmethyl or 1-piperidinylmethyl; R.sub.4 =hydrogen).
(B) Reacting the monoalkyl piperazine of general formula (II) with formaldehyde and a reactant selected from an amide of general formula R.sub.9 NH.sub.2 (IV) wherein R.sub.9 is 2-oxo-1-(pyrrolidinyl) acetyl, 2-hhydroxybenzoyl or 4-sulfamoylbenzoyl, thus obtaining the compounds of general formula (I) wherein R.sub.1 is defined above and R.sub.2 is --CH.sub.2 NHR.sub.9. These obtained compounds may be hydrolyzed, in an acid medium, to form the corresponding compounds of general formula (I) wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 NH.sub.2 which, by reaction with a carboxylic acid of general formula R.sub.9 OH (V) wherein R.sub.9 is as defined above, to provide the compounds of general formula (I) wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 NHR.sub.9.
(C) Reacting the monalkyl piperazine of general formula (II) with a carboxylic acid of general formula R.sub.10 COOH (VI) wherein R.sub.10 is 2-oxo-1-(pyrrolidinyl)methyl or 4-sulfamoylphenyl, thus obtaining the compounds of general formula (I) wherein R.sub.1 is as defined above and R.sub.2 is --COR.sub.10.
The reaction of the monalkyl piperazine of general formula (II) with the alkyl halides of general formula (III) is suitably conducted in a medium containing an alkanol having 1 to 4 carbon atoms, preferably ethanol, and in the presence of a base selected from either an alkali metal or alkaline earth metal carbonate or bicarbonate, preferably sodium bicarbonate, or a tertiary amine, preferably triethylamine, under reflux. Alkylation of N-monobenzhydrylpiperazine, morpholine or piperidine to yield the compounds of general formula (I) wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 --CR.sub.3 CHR.sub.4 (R.sub.3 =chloromethyl, R.sub.4 =hydrogen) is carried out in a medium containing an alkanol having 1 to 4 carbon atoms, preferably ethanol, under reflux, thus obtaining respective derivatives of compound I wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 --CR.sub.3 .dbd.CHR.sub.4 (R.sub.3 =(4-benzhydryl-1-piperazinyl)-methyl, 4-morpholinylmethyl or 1-piperidinylmethyl; R.sub.4 =hydrogen).
When the reaction is conducted between the monalkyl piperazine of general formula (II) and an amide of general formula (IV), in the presence of formaldehyde, it is convenient to use an alkanol having 1 to 4 carbon atoms as solvent, preferably ethanol, under reflux. Hydrolysis of the compounds thus obtained, in an acid medium, especially that formed from a mixture of acetic acid and hydrochloric acid, under reflux, leads to the fragmentation of the carboxamide group, thus obtaining the corresponding derivatives of compound I wherein R.sub.1 is as defined above and R.sub.2 =--CH.sub.2 NH.sub.2. The reaction of these derivatives with carboxylic acids of general formula (V) is conducted in the presence of carbonyldiimidazole as a catalyst in a medium composed of N,N-dimethylformamide, or an ether, preferably tetrahydrofuran, or mixture of both, and at room temperature, and results in derivatives of compound (I) wherein R.sub.1 is as defined above and R.sub.2 is --CH.sub.2 NHR.sub.9 (R.sub.9 =2-oxo-1-(pyrrolidinyl) acetyl, 2-hydroxybenzoyl or 4-sulfamoylbenzoyl.
In those cases where the reaction occurs between the monalkyl piperazine of general formula (II) and a carboxylic acid of general formula (VI), carbonylidiimidazole is also used as a catalyst and N,N dimethylformamide or an ether, preferably tetrahydrofuran, or a mixture thereof is used as a solvent.
Compounds of the present invention have cardiovascular properties and it should be emphasized a remarkable, i.e., marked, increasing effect on cerebral blood flow as experimentally determined by an electromagnetic flowmeter. Results of experimental cardiovascular assessment are shown hereinafter for the known substances Aligeron and Cinnarizine and for the active compounds (Tables 1 (i) and 1 (ii).
TABLE 1(i) ______________________________________ Mean arterial Antiarrythmic pressure, Heart rate, activity Hypotension Bradycardia Parameters ED.sub.50 (mg/Kg) ED.sub.50 (mg/kg) ED.sub.50 (mg/kg) Compounds 1- 2- 3- ______________________________________ 1 4.2 2.7 3.4 6 4.3 1.5 1.7 7 23.0 2.1 3.8 11 6.9 0.43 2.1 13 4.0 1.5 2.6 15 16.5 1.2 3.0 Cinnarizine 23.0 1.0 2.8 2HCI Aligeron-2HCI 4.4 1.3 4.8 ______________________________________ Cerebral Cerebral Carotid Arterial vascular flow flow pressure resistance Increase Decrease Decrease Decrease Parameters (%) (%) (%) (%) Compounds 4- 5- 6- 7- ______________________________________ 1 55.0 68.0 30.0 55.0 6 70.0 22.0 58.0 75.3 7 32.0 13.0 27.3 44.7 11 81.0 40.9 50.0 74.0 13 140.1 25.7 35.0 73.1 15 38.5 60.0 45.5 60.3 Cinnarizine 76.7 62.8 43.0 68.0 2HC1 Aligeron 2HCI 64.0 21.3 36.0 61.0 ______________________________________
Antiarrhythmic activity (Parameter 1) has been determined according to the method of Ferrini et al (Arzn.-Forsch., 29 (II), 9a, 1947-77, 1979). Compounds were endovenously administered to mice and results have been tabulated as ED.sub.50 values.
The decrease in arterial pressure (Parameter 2) and the effects on heart rate (Parameter 3) have been evaluated according to the usual conventional methods used in Cardiovascular Pharmacology. Compounds were endovenously administered to anesthetized rats and results have been tabulated as ED.sub.50 values.
The measurements of cerebral and carotid flow changes (parameters 4 and 5) have been made using the most sophisticated methods. Both parameters have been measured by electromagnetic flowmetry (Narcomatic-Electromagnetic flowmeter) on 12 anesthetized dogs. The hemodynamic parameter average of animals before testing were pO.sub.2 =95.40.+-.3.98; pCO.sub.2 =34.31.congruent.2.38 and pH-7.297.+-.0.315 by endovenously administering the compounds of a 5 mg/kg dosis.
Simultaneously with the measuring of cerebral and carotid flows, the mean arterial pressure and cerebral vascular resistance (parameters 6,7) in each animal was determined. These parameters were measured according to the conventional method in Cardiovascular Pharmacology and the values were tabulated as the variation rate (Increase or Decrease) over mean values before testing.
The toxicity of some compounds was determined and found to be lower than Aligeron and Cinnarizine which makes these compounds very useful in therapy. The LD.sub.50 was endovenously determined in mice according to the Reed-Muench's method as modified by Pizzi (Human Biology, 22(3), 151-190, 1950) and results are set out hereafter in comparison with Aligeron and Cinnarizine (Table 2).
TABLE 2 ______________________________________ Acute toxicity Compounds LD.sub.50 (mg/kg) ______________________________________ 1 25.6 .+-. 4.39 6 8.6 .+-. 0.54 7 100.0 .+-. 6.27 11 21.0 .+-. 1.72 13 42.5 .+-. 3.05 15 40.0 .+-. 4.19 Cinnarizine 2HCI 47.6 .+-. 5.25 Aligeron 2HCI 38.5 .+-. 1.06 ______________________________________
Compounds of the present invention mixed with pharmaceutically acceptable carriers can be administered by the oral route in the form of tablets, capsules, syrup, solution, etc., by injectible route and by rectal route, at daily doses ranging from 50 to 500 mg.